Amyotrophic lateral sclerosis (ALS) or Lou Gehrig disease is a fatal neurodegenerative disease that primarily affects mid-life and older adults. There are two forms of disease, familial (FALS) and sporadic (SALS), respectively comprising 10% and 90% of cases, respectively. The genetic causes of FALS have been linked to mutations in several genes such as superoxide dismutase, TDP-43, FUS, and optineurin. The etiology of SALS, however, remains elusive. A few years ago our laboratory found that there were polymorphisms in genes for enzymes called paraoxonases that were associated with SALS. Because these enzymes detoxify certain pesticides and toxic agents, they became the first environmentally related genes that were linked to ALS. Further studies of the paraoxonase enzymes PON1 and PON3 in the plasma indicate that their levels are significantly elevated in SALS patients, although the activities were similar. PON1 and 3 are found on high density lipoprotein (HDL) particles that contain multiple proteins with several functions including lipid and cholesterol transport and protecting lipoproteins from deleterious oxidation. Similar particles are also found in the cerebrospinal fluid (CSF). Thus, the objectives of this proposal are to further characterize HDL-particles in the plasma and CSF of SALS patients using high throughput technologies that can quantify the levels of multiple proteins present in these particles. Thus, we can determine for the first time how HDL particle composition changes in a neurodegenerative disease and if they are causally linked to the disease process. We will also determine whether the genes for the HDL-associated proteins contain variants that are associated with risk of SALS and whether these changes are related to alterations in HDL particle composition. Using advanced gene targeting techniques, we will create ApoL1 transgenic model mice to study the effects of over expressing this HDL component. The results from this work will open paths to therapies that seek to rescue potential dysfunctional HDL states found not only in neurodegenerative disease such as ALS but also in more common cardiovascular and metabolic diseases.